Diabetes requires an extremely precise form of daily treatment, whereby patients inject themselves with several doses of insulin every day.
Patients must therefore keep a supply of insulin which, according to pharmaceutical protocol, must respect the cold chain from production to injection. However, in some regions of the world like sub-Saharan Africa, not every household has a refrigerator.
This forces people living with diabetes to go to hospital on a daily basis. Faced with this issue, Médecins Sans Frontières (MSF) teamed up with the University of Geneva (UNIGE), Switzerland, to test insulin storage in real conditions, at temperatures ranging from 25 degrees C to 37 degrees C for four weeks.
This corresponds to the time it usually takes a diabetic person to finish one vial of insulin. The findings published in the journal PLOS ONE, demonstrate that the stability of insulin stored under these conditions is the same as that of cold-stored insulin, with no impact on efficacy. This allows people with diabetes to manage their illness without having to visit a hospital multiple times daily.
Type 1 diabetes is characterized by elevated blood sugar levels, which can have extremely serious consequences: coma, blindness, amputation or even death. Although it is now possible to treat type 1 diabetes well, it does require daily injections of insulin, which helps sugar enter the body’s cells.
“The current pharmaceutical protocol requires insulin vials to be stored between 2 and 8 degrees C until opened, after which most human insulin can be stored at 25 degrees C for four weeks,” explains Philippa Boulle, a non-communicable diseases advisor at MSF. “This is obviously an issue in refugee camps in temperatures hotter than this, where families don’t have refrigerators.”
People with diabetes thus often have to travel to a hospital every day for their insulin injections, which can prevent them from working or force them to travel long distances. “We turned to Professor Leonardo Scapozza’s team to undertake a detailed analysis of the temperature conditions under which insulin can be stored without a reduction in its efficacy,” says Dr. Boulle.
Real-life conditions
The MSF team in the Dagahaley refugee camp in northern Kenya found that the temperature in a home fluctuates between 25 degrees C at night and 37 degrees C during the day. The researchers then meticulously reproduced these conditions in laboratory setting, where they tested insulin storage. “
As you can insulin vials can be used for four weeks after opening, we carried out our measurements over the same timeframe, first with vials kept at the temperatures found in Dagahaley, and then with ‘control’ vials that were refrigerated,” explains Leonardo Scapozza, a professor of the School of Pharmaceutical Sciences in UNIGE’s Faculty of Sciences.
The UNIGE team used high-performance liquid chromatography to analyze the insulin. “The risk is that insulin, a protein, precipitates under the influence of heat.In other words, it would begin to form ‘flakes.” Since the insulin is no longer in solution, it can’t be injected.”
No difference between the two storage methods
The research results show that all the insulin preparations stored at fluctuating temperatures, as encountered in the field, recorded a potency loss of no more than 1%, just like those kept in cold storage during the required four weeks. “The regulation on pharmaceutical preparations allow a loss of up to 5%, so we are well below that,” says Professor Scapozza.
Crucially, the UNIGE researchers also observed that insulin activity was completely maintained. To verify this, they tested the action of insulin proteins on cells, compared with that of insulin that had been intentionally deactivated.
“Finally, with the help of Professor Michelangelo Foti’s group, we studied insulin vials that came directly from the Dagahaley camp, and always reached the same conclusion: the insulin was perfectly usable,” adds Professor Scapozza.
Results that may change the daily lives of thousands of people
This scientific study has shown for the first time that insulin vials can be used for four weeks even in hot weather without being refrigerated. “These results can serve as a basis for changing diabetes management practices in low-resource settings, since patients won’t have to go to hospital every day for their insulin injections,” states Dr. Boulle. In addition, people with diabetes would no longer be discriminated against and could lead normal lives and work.
“Of course, this will have to go hand-in-hand with educating patients, as well as providing support and follow-ups,” says Dr. Boulle, “so that people with diabetes can measure their blood sugar levels and inject the right amount of insulin. This will allow people to manage their illness correctly, and more independently. In support of this goal, we hope that a consensus statement will be drawn up, focusing on the at-home use of insulin in hightemperature settings when there is no refrigeration available, and that it will be endorsed by the WHO.”
After insulin is manufactured and transferred to pharmacies in a cold supply chain, patients with insulin-dependent diabetes are supposed to store their medication adequately under home conditions. Usually, insulin is stored in domestic refrigerators until first use and then carried as an opened pen or vial. So far, not much is known about how insulin is handled and stored once it leaves the controlled environment of the pharmacy. Given that patients store insulin at home before use, improper storage might have an impact on its potency at the point of use.
According to good distribution practice guidelines, storage conditions including temperature during storage and transit should be continuously monitored until the end of the cold supply chain to assure the quality of the drug.1–3 After manufacturers’ and the Food and Drug Administration’s (FDA) recommendations, insulin should ideally be stored in the refrigerator within a range of +2°C/36°F and +8°C/46°F for long-term storage until expiration date. Once taken out of the refrigerator, when opened or carried as a spare, it can be stored within +2°C/36°F and +25°C/77°F or +30°C/86°F, but should then be used within 4 to 6 weeks, depending on the product.4–7
Previous studies on home storage of other temperature sensitive medications have demonstrated that, even when leaflet instructions are being followed, the majority of patients do not always store their medication within the recommended temperature range. This was shown for antirheumatic biologic drugs, where the recommended temperature range of 2°C to 8°C was only maintained for 54.8% of storage time and only one in eight tumor necrosis factor antibodies was stored correctly in the refrigerator at home.8,9
Another study evaluated the suitability of domestic refrigerators for vaccine storage and found significant temperature disparities between different cooling zones within the same refrigerator. While some areas were shown to be warmer than recommended for medication storage, others were prone to freezing. “Dorm style” or “mini refrigerators” as they are frequently present in students’ homes or hotel rooms were shown to be unable to maintain temperatures between +2°C and +8°C over time and were therefore not recommended for storage of temperature sensitive drugs at all.10
Objective of our investigation was to analyze storage temperatures of insulin both kept in refrigerators and carried by patients, and to evaluate how often storage conditions do not meet the manufacturers’ recommendations regarding the temperature optimum.
Discussion
This evaluation shows that in daily life of patients with diabetes insulin was exposed to temperatures outside the recommended range to an extent that can be clinically relevant. Especially, refrigerated insulin was exposed to temperatures below the recommended range, even below freezing point.
These results are in line with other publications on storage conditions on domestic refrigerators for other types of temperature sensitive medication.8,9,11 However, to our knowledge, this is the first study investigating temperature conditions of insulin storage under home conditions of patients with diabetes in industrialized countries.
Optimal storage conditions of temperature sensitive drugs like insulin are crucial for their quality, that is, biological activity after subcutaneous administration. For people with diabetes who take insulin several times a day via injections or continuously administer insulin with a pump, precise dosing is essential to achieve optimal therapeutic outcomes. Even gradual loss of potency might introduce an unnecessary variability in insulin dosing and the insulin induced metabolic effects.
It is well known that the blood glucose-lowering effect of insulin is reduced when it was exposed to temperatures well outside the recommended range for longer periods of time.12–14 However, little information is publicly available about the impact on insulin potency of shorter or repeated temperature deviations below or above the recommended storage conditions.
While labels state storage temperature ranges and recommend to not use insulin after the formulation had been frozen, there are no further indications on how exposure to higher or lower temperatures for a certain time impacts insulin potency. The number of recent publications about the impact of temperature deviations on insulin potency is scarce.
Recently, a study indicated that insulin concentration in vials purchased randomly from pharmacies in the United States Midwest had insulin concentration well below the expected level of 95 U/mL required by the FDA.15,16 These findings have been challenged by others.17,18 Although there are documented cases of insulin that was rendered ineffective after exposure to heat and sunlight,12 other research states that insulin formulations are to an extent resistant to temperature excursions.
A possible reason for these different findings might be the method used to measure insulin potency. The FDA approved high performance liquid chromatography (HPLC) method was shown to be insensitive to structural changes induced by storage temperatures, which, however, might be of relevance for the metabolic activity.
Insulin was shown to maintain its quality when assessed by HPLC, size exclusion chromatography, and microscopy inspection after temperature excursions to heat (+45°C) and cold (−10°C) during 1 to 3 days long simulated transit conditions, which occur for mail order medications.13
A study conducted in India investigated insulin quality by HPLC and in vivo tests in rabbits after sustained storage at high temperatures. They found that insulin formulations started to lose bioactivity after 2 weeks exposed to temperatures of +32°C and +37°C.14 The standard method to assess insulin potency is HPLC, as recommended by the FDA. Other methods might be more sensitive toward the biological activity of peptides.
There is little publicly available data on the exact effects of storage temperature excursions on insulin potency and clinical outcomes. Some health authorities give recommendations for acceptable storage conditions in an emergency setting. The FDA, in their information for insulin storage in an emergency, acknowledges that insulin exposed to temperatures above 30°C could still be used if needed. Frozen insulin however, should not be used, even in an emergency.4 The East Africa Diabetes Study Group defines temperature limits of 0°C and 32°C as harmful for insulin quality in a setting where insulin and electricity are scarce.19
The mobile application used in this study sent notifications to the patient’s phone when temperature deviations were detected. As the patients might have reacted accordingly to prevent storage at inappropriate conditions, the time at which insulin is stored at too low or high temperatures might be underestimated. However, alarms were only triggered when the phone was within physical proximity to the sensor.
The participants in this evaluation have purchased temperature sensors on their own initiative and expense. Therefore, it is likely that the participants of this evaluation showed previous interest in the topic of medication storage and are likely to be aware of the temperature sensitivity of insulin. To avoid such a positive bias, it would be of interest to repeat this evaluation with a variety of patient populations. Furthermore, the low percentage of temperatures out of recommended range for carried insulin might have occurred due to possible little exposure to high temperature climates in the study cohort that was mainly located in countries in moderate climate zones. This might be different for study populations located in other climates or if temperatures were logged blinded without any temperature alarms given by the app.
Awareness of patients with diabetes about correct insulin storage has been researched before, although for populations living in hot climates. A survey from 2010 conducted in the southwestern United States found high awareness about heat sensitivity of insulin. Eighty percent of the participants correctly stated they start taking measures to protect their medication from ambient temperatures of +27.2°C/+81°F to 29.4°C/+85°F and up.20
Deviations from the recommended temperature range, especially below +2°C, occurred mostly for insulin stored in a refrigerator. This suggests that domestic refrigerators are at least intermittently too cold for medication storage, with an unknown impact of repeated excursions to temperatures over the course of several weeks or months on insulin quality. These results confirm the findings of previous studies that have demonstrated inadequate storage conditions for drugs in the refrigerator at home.8,9,11 While the label recommends storage between +2°C and +8°C, temperatures in most household refrigerators fluctuate over a wider range. A French study on food safety, showed a mean temperature fluctuation of 0.9 to 11.4 K in refrigerators, with an absolute minimum of −1.6°C and maximum of +12°C, depending on the placement of a temperature logger at the top, middle or bottom shelf.21
Various factors have potential influence on temperatures in a refrigerator compartment, making it difficult to give general recommendations on medication storage in the refrigerator. Factors that might influence medication storage temperature in refrigerators include: thermostat settings, placement of medication within the refrigerator, frequency of door openings, adjacent sources of heat (e.g. dishwashers), how full the refrigerator is and how different other items are arranged within the refrigerator, and type and age of the refrigerator.11,21 An investigation of home storage of biologic drugs found that refrigerators older than 5 years pose a risk factor for inadequate storage.11 The average household replaces its refrigerator every 7.8 years in the United Kingdom and every 14 to 18 years in the United States.21,22
The composition of warm and cold zones within a refrigerator depends on the type, for example, a compact refrigerator with one door and a top freezer or a large refrigerator with two doors and a separate freezer. As a temperature analysis of household refrigerators has shown, the coldest spot varies, and might be the top shelf for one type of refrigerator and the bottom drawer for another model.10,21,23 Furthermore, many domestic refrigeration systems are prone to a temperature drift toward cold temperatures. Especially, mini refrigerators as they are often found in hotel rooms and university dormitories have shown a severe drift to below freezing point, due to the lack of adequate air circulation.10 Furthermore, thermostat settings are not a reliable indicator for the actual refrigerator temperature.21
To choose the best placement and temperature setting for their medications, patients need to know about the location of warm and cold zones and the temperature progression over time of the refrigerator model in use. In the cold supply chain, this is managed by using qualified refrigerators and temperature monitoring systems. Temperature monitoring is a requirement for all steps in the distribution chain up to the point that medications are dispensed to the patient and could prove effective in reducing storage time outside the recommended temperature range for patients as well.1–3
Even in low and middle income countries with less resources, a thermometer is considered a necessity in refrigerators that store insulin.19 The use of data loggers with continuous temperature monitoring and alarms was shown to be superior over the use of a simple thermometer or a min-max thermometer in previous studies. An investigation of 120 household refrigerators in France showed no correlation between the temperatures measured using a thermometer at a given moment and using a data logger over a 7 day period.21 This is illustrated by the fluctuating temperature patterns detected by sensors in refrigerators. Also, the use of min-max thermometers, which are widely used in pharmacies, misses a number of temperature excursions, opposed to sensors with continuous monitoring.24–26
The data evaluated here were obtained from patients who were using temperature data sensors with alarms. A future investigation should compare storage conditions of insulin in domestic refrigerators before the use of such a temperature sensor and after intervention. Furthermore, more detailed information in the package leaflet for the given refrigerator about the different temperature zones is needed. Further investigations on the information sources publicly available, and pharmacists’ and patients’ awareness level on proper medication storage and patients’ distress concerning insulin quality might be of interest.
reference link: https://www.liebertpub.com/doi/10.1089/dia.2019.0046
What are the different types of insulin?
The American Diabetes Association (ADA) characterizes insulin by how fast it works. But everyone’s body is different. If you have diabetes, you should expect deviations in the amount of time any medication takes to reach your bloodstream.
- Onset is defined as the length of time before insulin hits your bloodstream and begins to lower blood glucose.
- Peak is the time during which insulin is at its maximum effectiveness at lowering your blood glucose levels.
- Duration is the length of time insulin continues to lower your blood glucose levels.
- Rapid-acting insulin begins to affect blood glucose approximately 15 minutes after injection. It peaks in about an hour, and then continues to work for a few more.
- Short-acting insulin reaches your bloodstream within 30 minutes of injection. It peaks in the 2-3-hour range and stays effective for 3-6 hours.
- Intermediate-acting insulin includes NPH insulin (neutral protamine hagedorn) which helps control glucose for 10-12 hours. A protamine is a type of protein that slows the action of this insulin.
- Long-acting insulin enters the bloodstream 1-2 hours after injection and may be effective for as long as 24 hours. An advantage to long-acting insulin is there is no pronounced peak, and it works more like typical pancreatic insulin.
- Premixed/combination insulin contains a mix of rapid- or short-acting insulin combined with an intermediate-acting insulin. This eliminates the need to draw insulin from more than one bottle.
How do you take insulin?
Many people with diabetes who use insulin self-administer it by injecting it with a syringe. The outside of the syringe is marked with lines denoting the amount of medication in the needle. There are different size syringes that you can choose from with the help of your doctor.
How do you choose the right syringe for injecting insulin?
- If your highest dose is near the syringe’s maximum capacity, consider buying the next size up in case your dosage increases
- If you measure your doses in half units, be careful to choose an appropriate syringe that has the right measurements
- When you’re traveling, make sure to match your insulin strength with the correct size syringe if you purchase new syringes in an unfamiliar place
Just as there are different sizes of syringes for administering insulin, there are also varying sizes of insulin needles. Shorter needles usually mean less sting when injecting. The downside is that the shallower the injection is, the longer it takes for the insulin to work. Your doctor will help you find the balance that’s best for you.
How do you take insulin without a syringe?
- Insulin pens look like large writing pens and can help prevent under- and overdosing. They also don’t require refrigeration, are conveniently prefilled, and are more durable than syringes.
- Insulin pumps are attached to a thin tube that’s implanted under your skin. Pumps are computerized or motorized, and some models also act as glucose monitors. They deliver insulin before each meal along with small amounts through the course of the day. In the US, about 60% of people with diabetes use some form of insulin pump.
- Jet injection devices are a good option if you hate needles. A jet injector holds several doses of insulin. After placing it against your skin, you press a button, and the insulin is pushed through.
- Inhalable insulin comes in a premeasured inhaler and was first approved in 2014. It’s short-acting and usually not covered by insurance, which makes it more cost prohibitive than other types of insulin for most people with diabetes.
Unless you have an insulin pump that also works as a glucose monitor, insulin dosing is based on self-monitoring your blood glucose levels. You can check them by doing finger pricks or wearing a device that continuously monitors them for you.
How should I store my insulin?
- Keep “current” insulin (like a few days or a week’s supply) at room temperature to help alleviate injection discomfort.
- Insulin can usually be stored at room temperature for about a month. Once in use, insulin pens should be stored at room temperature. Expiration dates of insulin pens can vary depending upon the type of insulin. For disposable pens, you should discard the entire device when empty or when you reach the expiration date.
- Store extra insulin (such as a 2–3-week supply or more) in the refrigerator.
- Don’t expose insulin to excessive cold or heat. (Don’t store it in the freezer or in direct sunlight.)
What are alternative medications for people with diabetes that aren’t insulin?
- Metformin – a pill that stops sugar production in the liver
- Glitazones – pills that remove sugar from the bloodstream
- Sufonylureas and glinides – pills that increase the release of insulin from your pancreas
- Starch blockers – pills that slow starch absorption
- Incretin therapies and amvlin analogs – pills and injections that reduce sugar production in the liver and slow food absorption. Types of the former include DPP4 inhibitors (such as Januvia) and GLP1 analogs (like Victoza).
- SGLT2 inhibitors – pills that are taken before meals that prevent the reabsorption of glucose
What else can I do to control my blood glucose levels?
Food, sleep, and exercise are all of vital importance for regulating your blood sugar when you have diabetes.
- Get enough sleep. Evidence shows that lack of sleep can lead to increased secretion of the hormone cortisol, which is inflammatory and can cause greater insulin resistance. Endocrinologist Al Powers MD of Vanderbilt University notes that when you’re deprived of sleep or your sleep is disrupted, your glucose levels tend to go up, whether you have diabetes or not.
- Exercise regularly. During exercise, insulin sensitivity is increased, and muscle cells use available insulin more efficiently. When your muscles contract during exercise, they also absorb glucose and use it for energy.
- Follow a diabetic-safe diet recommended by your doctor with limited carbohydrates, such as the DASH diet or the Mediterranean diet. Both have been shown to help stabilize blood sugar levels.
What severe complications can occur because of rationing or running out of insulin?
Diabetic ketoacidosis is an emergency condition that results if you don’t have enough insulin to regulate your blood sugar. DKA causes your body to break down fat for energy in the absence of insulin. This leads to a dangerous accumulation of acids known as ketones in your blood that can cause your brain to swell and your body to go into shock.
Signs of diabetic ketoacidosis include:
- Thirst or a very dry mouth
- Frequent urination
- High blood sugar levels
- High levels of ketones in your urine
- Fatigue
- Dry or flushed skin
- Nausea, vomiting, or stomach pain
- Difficulty breathing
- A fruity or acetone odor on your breath (yes, just like nail polish remover)
- Confusion or acting “drunk” while sober
DKA is so common and can come on so quickly that it is the first sign of Type 1 diabetes in 20% of cases, and the way many type 1 diabetics are first diagnosed with the condition. If you go into diabetic ketoacidosis, don’t try to hide it or make light of it. Treat it as the emergency it is and get to a hospital as soon as possible to recover. “I’ve had people tell me they’re tired of taking insulin, or that they’re rationing it due to cost. In type 1 diabetes, that’s all it takes to end up in a life-threatening situation,” says Dr. Zilbermint.
Another complication facing diabetics who use insulin is the potential for hyperglycemia, also known as “insulin shock,” which involves using too much insulin and causing your blood sugar to drop extremely low. “This can cause coma, seizures, and heart attacks,” says Dr. Powers.
The good news? Once you get to a hospital, doctors can stabilize both conditions quickly, so take them seriously, and make sure your friends and family are educated about your diabetes. Your chosen support network should know how to spot the signs and get you to medical help immediately if you need it and aren’t feeling well enough to advocate for yourself.
More information: PLOS ONE (2021). DOI: 10.1371/journal.pone.0245372
